COPD is the 4th leading cause of death, costing $37 billion/year in the US. Existing diagnostic methods, while valuable, do not distinguish among specific pulmonary pathophysiological components, thereby compromising informed treatment and sensitive observation of disease progression. We recently developed MRI methods utilizing hyperpolarized 129-Xenon that allow noninvasive measurement of three important pulmonary function parameters. These are (a) alveolar surface area per unit volume, loss of which is a direct measure of emphysema;(b) septal thickness, increases in which reflect interstitial disease;and (c) blood transit time through the gas exchange region, altered in the presence pulmonary vascular disease. The ability to obtain these measures of pulmonary function with a noninvasive method that does not use ionizing radiation is novel and unprecedented. We propose to demonstrate the utility of these methods for the characterization of COPD subjects. The cost of this study will be substantially reduced as it is an ancillary study of an already funded NIH study, named COPDGene that is investigating causal genetic factors for COPD. COPDGene is obtaining spirometry, CT and symptomatic questionnaire data on 10,500 smokers with a range of lung function. We will study 130 subjects from this cohort. Our aims will be to create a database of the hyperpolarized 129Xe measured quantities from smokers with normal function and then to measure deviations from this normative database for subjects with GOLD Stage 1-3 disease. We will do this both with whole lung data and with an imaging approach that will allow measurement of disease heterogeneity regionally within each subject. Our goal is to demonstrate that 129Xe measures of pulmonary function are more highly correlated with symptomatic measures of pulmonary physical distress than existing measures of pulmonary function. PUBLIC HEALTH RELEVANCE: We propose studies to test a new, noninvasive technique to determine whether or not it can more clearly identify the specific causes of lung disease, specifically Chronic Obstructive Pulmonary Disease (COPD). The new technique uses a novel MRI contrast agent, known as hyperpolarized xenon-129 gas. The proposed research will determine what is a normal range of values with the new test, then measure the deviation from this normal range of values in subjects with lung disease, and compare the new test's predictive value for disease with current tests used by lung doctors.